Systems biology, "the sciences of the 21st century", is an interdisciplinary challenge for biologists, computer scientists, system theoreticians, and physicians. The "Systems" approach aims to capitalize on the dramatic advances in proteomics, genomics, and measurement technologies such as DNA arrays to generate a holistic understanding of biological organisms. Systems biology approaches can be profitably exploited to investigate the interaction of pathogens with their hosts. An essential first step is to identify host and pathogen genetic traits that contribute to important disease properties such as virulence. Forward genetic approaches permit the unbiased identification of Quantitative Trait Loci (QTL) of the host. The identification of potential relevant genes and pathways within QTL can then be integrated into high throughput experimental designs to identify RNA and protein expression profiles coupled with mathematical modeling and bioinformatics to assemble refined testable models of pathogenesis. Further refinement of the models is expected to yield insights into potential new preventative and treatment options, biomarkers predictive of disease susceptibility and severity, and importantly, personalized medical risk assessment and treatment strategies. At UC and CCHMC we have established strong programs in systems biology, an important new aspect of which is the establishment of a colony of the C57Blk/6xDBA/2 Advanced Recombinant Inbred strains. Thus we have >100 lines of fully genetically characterized ARI mice. Over the past 2 decades we have developed and characterized murine models of all facets of herpes simplex virus (HSV) pathobiology, pioneered strategies to quantify disease processes at the singe cell level and generated a large stable of defined viral mutants. We will combine these approaches in an unbiased forward "Systems Genetics" approach to identify host genes and pathways that moderate all phases of viral pathogenesis. This approach will identify common pathways and networks that affect disease severity that are anticipated to translate directly into improved individualized treatment and prevention strategies for viral infections in general, and reveal biomarkers and potential targets shared by many viral pathogens. PUBLIC HEALTH RELEVANCE: Infections by bacteria, viruses, fungi, and other parasites cause death in an estimated 17 million individuals per year worldwide. There is a great need for the identification of new targets that could provide the basis for the development of novel broad spectrum antimicrobial agents. The proposed research will use a forward genetic analysis to identify the network of host pathways regulating disease susceptibility and resistance. This information will identify potential targets for broad spectrum antimicrobial agents.